Nivolumab treatment beyond RECIST-defined progression in recurrent or metastatic squamous cell carcinoma of the head and neck in CheckMate 141: A subgroup analysis of a randomized phase 3 clinical trial

BACKGROUND: Response patterns with immune checkpoint inhibitors may be different from those with chemotherapy. Therefore, assessment of response to immunotherapy with the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, could result in premature treatment termination. The randomized, open-label, phase 3 CheckMate 141 trial (NCT02105636), which evaluated nivolumab in recurrent/metastatic squamous cell carcinoma of the head and neck after platinum therapy, allowed treatment beyond first RECIST-defined progression (TBP) according to protocol-specified criteria. METHODS: In CheckMate 141, patients with RECIST-defined progression who had a stable performance status and demonstrated clinical benefit without rapid disease progression were permitted to receive TBP with nivolumab at 3 mg/kg every 2 weeks until further progression, which was defined as an additional 6510% increase in tumor volume. This post hoc analysis evaluated outcomes for patients who received TBP with nivolumab. RESULTS: Of 240 patients randomized to nivolumab, 146 experienced RECIST-defined progression. Sixty-two of these patients received TBP, and 84 discontinued treatment (no TBP). Among the 60 TBP patients evaluable for response, 15 (25%) had no change in their tumor burden, and 15 (25%) had reductions in target lesion size; 3 patients (5%) had reductions >30%. The median overall survival among TBP patients was 12.7 months (95% confidence interval, 9.7-14.6 months). No new safety signals were observed with TBP. Exploratory analyses of immune cell biomarkers suggested a potential relationship with initial and TBP responses. CONCLUSIONS: Tumor burden reduction was noted in a proportion of patients who received TBP with nivolumab in CheckMate 141. Additional research is warranted to identify factors predictive of a TBP benefit in this population

Human Health Risk Assessment For Arsenic: A Critical Review

Millions of people are exposed to arsenic resulting in a range of health implications.This paper provides an up-to-date review of the different sources of arsenic (water, soil and food), indicators of human exposure (biomarker assessment of hair, nail, urine and blood), epidemiological and toxicological studies on carcinogenic and non-carcinogenic health outcomes, and risk assessment approaches. The review demonstrates a need for more work evaluating the risks of different arsenic species such as; arsenate, arsenite monomethylarsonic acid, monomethylarsonous acid, dimethylarsinic acid and dimethylarsinous acid as well as a need to better integrate the different exposure sources in risk assessments

Planar cell polarity signalling regulates cell adhesion properties in progenitors of the zebrafish laterality organ

Organ formation requires the precise assembly of progenitor cells into a functional multicellular structure. Mechanical forces probably participate in this process but how they influence organ morphogenesis is still unclear. Here, we show that Wnt11- and Prickle1a-mediated planar cell polarity (PCP) signalling coordinates the formation of the zebrafish ciliated laterality organ (Kupffer's vesicle) by regulating adhesion properties between organ progenitor cells (the dorsal forerunner cells, DFCs). Combined inhibition of Wnt11 and Prickle1a reduces DFC cell-cell adhesion and impairs their compaction and arrangement during vesicle lumen formation. This leads to the formation of a mis-shapen vesicle with small fragmented lumina and shortened cilia, resulting in severely impaired organ function and, as a consequence, randomised laterality of both molecular and visceral asymmetries. Our results reveal a novel role for PCP-dependent cell adhesion in coordinating the supracellular organisation of progenitor cells during vertebrate laterality organ formation

Nivolumab in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck: Efficacy and Safety in CheckMate 141 by Prior Cetuximab Use

PURPOSE: Cetuximab, which modulates immune responses, may affect the efficacy of subsequent immunotherapy. Here, we assessed outcomes with nivolumab, by prior cetuximab exposure, in patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) who had experienced progression within 6 months of platinum-containing chemotherapy. EXPERIMENTAL DESIGN: In the randomized, open-label, phase III CheckMate 141 trial, patients were randomized 2:1 to nivolumab 3 mg/kg every 2 weeks or investigator's choice (IC) of single-agent chemotherapy, with stratification by prior cetuximab exposure. The primary endpoint was overall survival (OS); additional endpoints were progression-free survival, objective response rate, and safety. RESULTS: In patients with prior cetuximab exposure, the median OS was 7.1 months with nivolumab versus 5.1 months with IC (HR, 0.84; 95% CI, 0.62-1.15); OS benefit with nivolumab was maintained across most demographic subgroups. In patients without prior cetuximab exposure, the median OS was 8.2 months with nivolumab versus 4.9 months with IC (HR, 0.52; 95% CI, 0.35-0.77); OS benefit with nivolumab was maintained across patient baseline subgroups including tumor programmed death ligand 1 (PD-L1) expression (<1% or 651%). Grade 3-4 treatment-related adverse event rates favored nivolumab versus IC in both subgroups. CONCLUSIONS: Nivolumab appeared to improve efficacy versus IC regardless of prior cetuximab use, supporting its use in patients with R/M SCCHN with or without prior cetuximab exposure. The reduction in risk of death with nivolumab compared with IC was greater in patients without prior cetuximab exposure versus with prior cetuximab exposure

Atlanto Iberian sardine spawning stock biomass during 2014 DEPM survey (ICES areas IXa and VIIIc)

The present document includes an update on the results from the Atlanto Iberian sardine 2014 DEPM survey submitted to the WGACEGG in November 2014. For the preliminary SSB estimates presented at the 2014 meeting, an average spawning fraction value (using the whole series data) was considered for the southern (Algarve and Cadiz Bay) and western strata (western Portugal) since the information collected during the 2014 campaign in those areas was not fully processed. Detailed sampling and laboratorial methodology and survey description including environmental characterization and sampling effort can be found in the 2014 WGACEGG repor